Synthesis of spiro-oxindoles catalyzed by nano-Co3S4

Article abstract of DOI:10.1007/s00706-018-2246-3

Abstract: A simple method for the synthesis of spiro[pyrazoloquinoline-oxindoles] and spiro[chromenopyrazolo-oxindoles] has been achieved through four-component reactions of phenylhydrazine or hydrazine hydrate, isatins, ketoesters, and naphthylamine or 2-naphthol using nano-Co₃S₄ under ultrasonic irradiations. The current method provides obvious positive points such as environmental friendliness, significantly shorter reaction time, markedly excellent yields, and simple workup procedure. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-018-2246-3

Monatshefte für Chemie - Chemical Monthly
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ORIGINAL PAPER
Synthesis of spiro-oxindoles catalyzed by nano-Co3S4
Hossein Shahbazi-Alavi1
Fatemeh Alemi-Tameh2 Javad Safaei-Ghomi1
•
•
Received: 17 February 2018 / Accepted: 28 May 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
A simple method for the synthesis of spiro[pyrazoloquinoline-oxindoles] and spiro[chromenopyrazolo-oxindoles] has been
achieved through four-component reactions of phenylhydrazine or hydrazine hydrate, isatins, ketoesters, and naphthy-
lamine or 2-naphthol using nano-Co3S4 under ultrasonic irradiations. The current method provides obvious positive points
such as environmental friendliness, significantly shorter reaction time, markedly excellent yields, and simple workup
procedure.
Graphical abstract
Keywords Nanocatalyst Á Oxindoles Á One-pot Á Multi-component Á Ultrasonic conditions
Introduction
preparation of spirooxindoles has been reported in the
presence of catalysts including p-toluenesulfonic acid (p-
TSA) [11, 12], piperidine [13], alum (KAl(SO4)2Á12H2O)
[14], amino-functionalized SBA-15 (SBA-Pr-NH2) [15],
nanocrystalline MgO [16], and L-Proline [17]. However,
some of the developed ways endure drawbacks including
long reaction times, low yields, and harsh reaction condi-
tions [11–17]. To elude these restrictions, the discovery of
an efficient, easily accessible catalyst with high catalytic
activity for the preparation of spirooxindoles is still
favored. The combination of multi-component reactions
with a suitable catalyst could expand their effectiveness
from operating cost and conservation points of view [18].
The heterogeneous catalysts could be recovered by easy
operations and reused many times without significant loss
of its catalytic activity. In addition, the high surface-to-
volume ratio of nanoparticles provides a larger number of
active sites per unit area compared to their heterogeneous
counterparts [19–21]. Recently, several nanocatalysts have
been applied for the preparation of organic compounds
under ultrasonic conditions [22–24]. Actually, the
Spirooxindoles have emerged as a group of important
heterocycles due to their presence in a broad spectrum of
natural and synthetic organic compounds [1–3], with
diverse biological properties such as antimicrobial [4–6],
antitumor [7, 8] and antidiabetic [9], and can also serve as
synthetic intermediates for diverse kinds of pharmaceuti-
cals or drug precursors [10]. These activities make
spirooxindoles appealing goals in organic synthesis. The
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-018-2246-3) contains
supplementary material, which is available to authorized
users.
& Hossein Shahbazi-Alavi
hossien_shahbazi@yahoo.com
1
Department of Organic Chemistry, Faculty of Chemistry,
University of Kashan, Kashan, Iran
2
Department of Chemistry, Science and Research Branch,
Islamic Azad University, Tehran, Iran
123

H. Shahbazi-Alavi et al.
application of ultrasound in the organic synthesis has been
expanding on account of its significant benefits such as
milder reaction condition, shorter reaction times, and
excellent yields in comparison with the classical methods
[25, 26]. In the current study, we investigated an easy
method for the synthesis of spiro[pyrazoloquinoline-oxin-
doles] and spiro[chromenopyrazolo-oxindoles] through a
four-component reactions of phenylhydrazine or hydrazine
hydrate, isatins, ketoesters, and naphthylamine or 2-naph-
thol using nano-Co3S4 under ultrasonic irradiations
(Scheme 1).
enhancing number of active cavitation bubbles and size of
the individual bubbles. Both of which are expected to result
in higher maximum collapse temperature and accelerate the
synthesis of spiro-oxindoles. Spiro-oxindoles were pre-
pared by nano-Co3S4 using the obtained optimized condi-
tion (Table 2). To check the scope and limitation of this
catalytic process, phenylhydrazine or hydrazine hydrate,
isatins, ketoesters, and naphthylamine or 2-naphthol were
chosen as substrates. Investigations of the reaction scope
revealed that various isatins can be utilized in this protocol
(Table 2).
The reusability of nano-Co3S4 was checked for the
reaction of hydrazine hydrate, 5-chloroisatin, ethyl ace-
toacetate and 2-naphthol, and it was found that product
yields decreased to a small extent on each reuse (run 1,
94%; run 2, 94%; run 3, 93%; run 4, 93%; run 5, 92%; run
6, 92%). After completion of the reaction (TLC), acetone
was added. The catalyst was insoluble in acetone, and it
could be recycled by filtration. The solvent was then
evaporated and the solid obtained recrystallized from
ethanol to afford the spirooxindoles. The recovered nano-
Co3S4 was washed five to seven times with ethanol and
dried at room temperature for 20 h. The heterogeneous
catalysts could be recovered by easy operations and reused
many times without significant loss of its catalytic activity.
In addition, the high surface-to-volume ratio of nanopar-
ticles provides a larger number of active sites per unit area
compared to their heterogeneous counterparts. The extreme
stability of the nano-Co3S4 is mainspring of the continuous
and high catalytic activity. In this mechanism, the surface
atoms of nano-Co3S4 activate the C=O groups for better
reaction with nucleophiles. These surface atoms behave as
the centers where the chemical reactions could be cat-
alytically stimulated. It has been observed that better yields
Results and discussion
The XRD patterns of Co3S4 nanoparticles agreed well with
the reported pattern (JCPDS No. 73-1703) (Fig. 1). Our
SEM image showed particles with diameters in the
nanometer range (Fig. 2). Energy-dispersive spectroscopy
(EDS) confirmed the presence of Co and S (Fig. 3).
Beforehand, we optimized various reaction parameters
for the synthesis of spirooxindoles by the condensation
reaction of hydrazine hydrate, 5-chloroisatin, ethyl ace-
toacetate, and 2-naphthol as a model reaction. And now,
the effect of experimental factors comprising type and
amount of catalyst and solvent were investigated to find the
best condition for this reaction and the results are listed in
Table 1. The best results were obtained in ethanol and we
found that the reaction gave satisfying results in the pres-
ence of nano-Co3S4 which gave excellent yields of prod-
ucts under ultrasonic irradiation (40 W) (Table 1). In this
research, ultrasound irradiation is used as green and com-
plementary techniques for preparation of spiro-oxindoles.
Essentially, the main role of ultrasound irradiation is
Scheme 1
123

Synthesis of spiro-oxindoles catalyzed by nano-Co3S4
Fig. 1 XRD pattern of nano-Co3S4
Fig. 3 EDS of nano-Co3S4
Conclusion
In conclusion, we have reported an efficient way for the
synthesis of spirooxindoles using nano-Co3S4 under ultra-
sonic irradiations. The current method provides obvious
positive points such as environmental friendliness, signifi-
cantly shorter reaction time, markedly excellent yields and
simple workup procedure. In our opinion, we expect this
method will find extensive applications in the field of
combinatorial chemistry, diversity-oriented synthesis, and
sonochemistry.
Fig. 2 SEM image of nano-Co3S4
are achieved with substrates having electron-withdrawing
groups.
A
reasonable mechanism for the synthesis of
spirooxindoles using nano-Co3S4 is shown in Scheme 2.
The mechanism involves the initial nucleophilic attack of
hydrazine on the ethyl acetoacetate to form the interme-
diate I and then, the reaction of isatin with intermediate I to
give intermediate II. In the next step, the reaction can be
followed by attack of the naphthylamine or 2-naphthol that
leads to the formation of III and IV. The final product is
formed by the intra-molecular cyclization reaction. This
mechanism has been supported by literature [11].
Experimental
The products were isolated and characterized by physical
1
and spectral data. H NMR and 13C NMR spectra were
recorded on Bruker Avance 400 MHz spectrometers in the
presence of tetramethylsilane as internal standard. The IR
spectra were recorded on FT-IR Magna 550 apparatus
using with KBr plates. Melting points were determined on
123

H. Shahbazi-Alavi et al.
Table 1 Optimization of
reaction conditions using
different catalysts
Entry
Solvent
Catalyst
Time/min)
Yieldb/%
1
EtOH (reflux)
–
200
120
120
120
120
120
120
120
120
120
120
120
10
Trace
17
32
38
22
51
45
54
65
72
80
80
85
90
94
94
92
2
EtOH (reflux)
CAN (5 mol%)
3
EtOH (reflux)
NaHSO4 (10 mol%)
Et3N (10 mol%)
4
EtOH (reflux)
5
EtOH (reflux)
Fe3O4 NP (50 mg)
TsOH (20 mol%)
nano-Co3S4 (20 mg)
nano-Co3S4 (20 mg)
nano-Co3S4 (20 mg)
nano-Co3S4 (10 mg)
nano-Co3S4 (20 mg)
nano-Co3S4 (30 mg)
nano-Co3S4 (10 mg)
nano-Co3S4 (8 mg)
nano-Co3S4 (10 mg)
nano-Co3S4 (12 mg)
nano-Co3S4 (10 mg)
6
EtOH (reflux)
7
H2O (reflux)
8
DMF (reflux)
9
CH3CN (reflux)
EtOH (reflux)
10
11
12
13
14
15
16
17
EtOH (reflux)
EtOH (reflux)
EtOH (US: 30 W)a
EtOH (US: 40 W)
EtOH (US: 40 W)
EtOH (US: 40 W)
EtOH (US: 50 W)
10
10
10
10
Hydrazine hydrate (1 mmol), 5-chloroisatin (1 mmol), ethyl acetoacetate (1 mmol), and 2-naphthol
(1 mmol)
Bold values indicate the best result in reaction conditions
aUltrasonic irradiation
bIsolated yield
Table 2 Synthesis of spirooxindoles by nano-Co3S4 (10 mg) under ultrasonic irradiation (40 W)
Entry
Isatins R
R0
R00
4a or 4b
Product
Time/min
Yielda/%
M.p./°C found
M.p./°C literature
1
2
3
4
5
6
7
8
Cl
H
H
Me
Me
Me
Me
Me
Me
n-Pr
n-Pr
4a
4a
4a
4a
4b
4b
4b
4b
5a
5b
5c
5d
6a
6b
6c
6d
10
15
10
10
10
10
15
10
94
92
89
94
88
91
86
89
196–198
185–187
171–173
190–192
255–258
262–264
300–302
295–297
–
H
–
Me
NO2
H
H
–
H
–
Ar
Ar
Ar
Ar
255–258 [11]
264–267 [11]
304–307 [11]
298–301 [11]
Cl
H
Cl
aIsolated yield
Electrothermal 9200. The elemental analyses (C, H, N)
were obtained from a Carlo ERBA Model EA 1108 ana-
lyzer. Powder X-ray diffraction (XRD) was performed on a
Philips diffractometer X’pert Company with monochrom-
Preparation of nano-Co3S4
In a typical preparation, molar ratios (1:3) of Co(CH3-
COO)2Á4H2O and thioglycolic acid were mixed in 200 cm3
distilled water with constant stirring. After 30 min stirring,
the final solution was washed in a 200-cm3 teflon-lined
stainless steel autoclave and heated at 180 °C for 45 h in an
oven. The product was washed with distilled H2O and
absolute EtOH several times to remove excessive reactants
and by-products, followed by drying in an oven at 80 °C
for 8 h.
˚
atized Cu Ka radiation (k = 1.5406 A). Microscopic mor-
phology of products was visualized by SEM (MIRA 3
TESCAN). A multiwave ultrasonic generator (Sonicator
3200; Bandelin, MS 73, Germany) was utilized for the
ultrasonic irradiation.
123

Synthesis of spiro-oxindoles catalyzed by nano-Co3S4
Scheme 2
136.70 (CH), 137.92 (C), 142.56 (CH-C–Cl), 156.70 (CH-
C-O), 163.74 (C=O) ppm.
General procedure for the synthesis
of spirooxindoles
10-Methyl-8H-spiro[benzo[5,6]chromeno[2,3-c]pyrazole-
11,30-indolin]-20-one (5b, C22H15N3O2) Yellow powder;
A mixture of isatin derivatives (1 mmol), phenylhydrazine
or hydrazine hydrate (1 mmol), alkyl acetoacetate
(1 mmol), naphthalene amine or 2-naphthol (1 mmol), and
10 mg nano-Co3S4 was sonicated at 40 W power for the
appropriate times. The reaction was monitored by TLC (n-
hexane/ethyl acetate 8:2). After cooling, the reaction
mixture was dissolved in acetone and the mixture stirred
for 2 min. The suspended solution was filtered and the
heterogeneous catalyst was recovered. The acetone was
evaporated and the solid that separated out was filtered and
washed with ethanol to get pure product.
ꢀ
m.p.: 185–187 °C; IR (KBr): m = 3215.9, 3097.1, 2917.4,
1618.0, 1473.3 cm-1 1H NMR (400 MHz, DMSO-d6):
;
d = 1.92 (s, 3H, CH3), 6.45 (d, J = 7.6 Hz, 2H, ArH), 6.75
(d, J = 8.0 Hz, 2H, ArH), 6.86-6.94 (m, 2H, ArH), 6.96-
7.21 (m, 4H, ArH), 10.18 (s, 1H, NH-CO), 11.20 (s, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.10
(CH3), 49.07 (C), 106.72 (C), 111.07 (C), 112.09 (CH),
117.34 (2CH), 120.13 (CH), 123.20 (2CH), 124.37 (CH),
125.99 (CH), 126.90 (CH), 128.63 (C), 128.82 (CH),
130.66 (C), 133.92 (C), 135.90 (C), 137.00 (C), 141.33 (C),
156.60 (CH-C-O), 165.07 (C=O) ppm.
50-Chloro-10-methyl-8H-spiro[benzo[5,6]chromeno[2,3-
c]pyrazole-11,30-indolin]-20-one (5a, C22H14ClN3O2) Yel-
50,10-Dimethyl-8H-spiro[benzo[5,6]chromeno[2,3-c]pyra-
zole-11,30-indolin]-20-one (5c, C23H17N3O2) Yellow pow-
ꢀ
low powder; m.p.: 196–198 °C; IR (KBr): m = 3321.4,
1
3222.5, 2927.4, 2852.2, 1618.5, 1423.3 cm-1; H NMR
ꢀ
der; m.p.: 171–173 °C; IR (KBr): m = 3222.5, 3104.8,
(400 MHz, DMSO-d6): d = 1.86 (s, 3H, CH3), 6.69 (d,
J = 8.0 Hz, 2H, ArH), 7.05-7.64 (m, 6 H, ArH), 7.74 (s,
1H, ArH), 10.24 (s, 1H, NH-CO), 11.25 (s, 1H, NH) ppm;
13C NMR (100 MHz, DMSO-d6): d = 10.13 (CH3), 48.80
(C), 108.70 (C), 111.09 (C), 117.51 (CH), 120.28 (2CH),
123.20 (CH) 124.51 (C), 125.90 (2CH), 125.99 (2C),
128.35 (C), 130.74 (CH), 133.93 (C–Cl), 133.98 (C),
2900.2, 1634.2, 1517.3, 1335.4 cm-1; 1H NMR (400 MHz,
DMSO-d6): d = 1.79 (s, 3H, CH3), 2.25 (s, 3H, CH3), 7.03-
6.05 (m, 4H, ArH), 7.60 (d, J = 8.4 Hz, 2H, ArH), 7.11-
8.13 (m, 3H, ArH), 10.18 (s, 1H, NH-CO), 11.35 (s, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.19
(CH3), 23.45 (CH3), 49.10 (C), 107.75 (C), 112.04 (C),
112.18 (CH), 117.44 (2CH), 120.22 (CH), 123.25 (2 CH),
123

H. Shahbazi-Alavi et al.
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124.41 (C), 125.90 (C), 126.84 (CH), 128.74 (CH), 128.84
(C), 130.72 (CH), 133.94 (C), 135.96 (C), 137.21 (C),
141.43 (C), 156.64 (CH-C-O), 165.12 (C=O) ppm.
10-Methyl-50-nitro-8H-spiro[benzo[5,6]chromeno[2,3-
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ꢀ
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2968.3, 2869.6, 1608.3 cm-1 1H NMR (400 MHz,
;
DMSO-d6): d = 1.88 (s, 3H, CH3), 6.92-6.98 (m, 2H, ArH),
7.14-7.18 (m, 6H, ArH), 7.92 (s, 1H, ArH), 10.24 (s, 1H,
NH-CO), 11.25 (s, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 10.18 (CH3), 48.78 (C), 107.78 (C),
111.29 (C), 117.63 (2CH), 120.38 (CH), 124.22 (2CH),
124.55 (CH), 125.93 (C), 126.80 (CH), 128.10 (CH),
128.25 (CH), 130.87 (C), 133.76 (C), 134.57 (C), 137.88
(C), 139.62 (C), 143.42 (C-NO2), 156.62 (CH-C-O),
163.95 (C=O) ppm.
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